Although Graves' ophthalmopathy (GO), a disorder frequently associated with hyperthyroidism, is immunologically mediated the underlying mechanisms are poorly understood and specific autoantigens and their corresponding circulating autoantibodies have not, until recently, been identified. The primary site of the inflammation is in the extraocular muscles. Whilst progressive eye muscle damage is likely to be mediated by killer (K) cells in association with autoantibodies against and eye muscle cell-furface antigen(s) the measurement of other antibodies may be useful as markers of the autoimmune process. Our recent demonstration of serum autoantibodies directed against soluble and membranous eye muscle antigens in patients with active GO provides strong evidence for an autoimmune pathogenesis for this disorder. In the present study we will further investigate the pathogenetic and clinical significance of these antibodies. The appearance of eye muscle antibodies in patients with Graves' hyperthyroidism, before the onset of eye involvement, would suggest a role of antibody testing in predicting those patients likely to develop ophthalmopathy, whilst close correlation between antibody levels and severity of the eye muscle involvement would raise the possibility that antibody measurement could be used to monitor treatment. Eye muscle autoantibodies will be tested for direct and K cell-mediated cytotoxic effect on cultured human eye muscle cells. The corresponding autoantigens will be purified from crude preparations, using monoclonal antibodies reactive with the specific antigens, and characterized in respect to tissue and species distribution, intracellular site, MW and chemical composition. The possible existence of autoantibodies against eye muscle cell surface antigens and other membranous and soluble antigens will be studied in the same way. These studies should provide not only important information in respect to our understanding of the pathogenesis of the eye muscle involvement of Graves' ophthalmopathy, but also, simple antibody tests for uses as aids in the diagnosis and management of patients with this disorder.